Our laboratory studies the differences in lung cancer risk among cigarette smokers. We have assessed the association between inherited susceptibilities for carcinogen metabolism and the formation of DNA adducts. In a study of lung tissues from 90 people, we found that the GSTM1 null genotype was associated with polycyclic aromatic hydrocarbon-DNA adducts, and that both CYP2D6 and CYP2E1 polymorphisms were associated with 7-methyl-dGp adducts, the latter of which varied by smoking exposure. This is consistent with other data, but here we demonstrated the association in vivo and in a target tissue. In this small dataset, it was also found that smoking women compared to men, and smoking African Americans compared to Caucasian Americans had a higher level of 7-alkyl-dGp adducts, consistent with a higher risk of lung cancer in these groups, for similar levels of smoking. We also determined the distribution of 7-alkyl-dGp adducts in human lung in order to determine if random biopsies were reflective of total lung adduct levels. We found that this was the case for 70% of study subjects, but that 30% had widely varying levels. This level of misclassification will reduce the statistical power further for small studies. A study has been conducted in order to determine the frequency of genetic polymorphisms in 100 elderly smoking subjects without a history of cancer. We hypothesized that some genetic polymorphisms confer an increase risk, then the frequency of these "at risk" alleles should be markedly decreased in elderly smokers who have "escaped" smoking related cancers. We found that a genetic polymorphism in the Apolipoprotein E gene, associated with longevity, was also increased in the smokers. Thus, the effects of smoking does not influence the hypothesized effects of the gene. We also have studied lung cancer risk among non-smoking Chinese women, who have similar cancer rates among U.S. women. In order to explore the molecular epidemiology of lung cancer, we have initiated a study of non-smoking Chinese women as a subset of a 2,000 women case-control study. Thus far, this study has replicated the previous finding that there is an increased risk of wok cooking with rapeseed oil and for use of coal for heating and cooking in the home. Currently these exposures are being studied in the context of CYP1A1, CYP2E1, GSTM1, CYP2D6, APOE, and GST-T genetic polymorphisms.